Free-Radical Cyclization

Free-radical cyclization in the synthesis of N-heterocycles 97T17543. 

Intramolecular cyclization of sulfonyl radicals is almost absent from literature. The fact that free radical cyclization has been the subject of a large number of studies and applications in the last decade in organic chemistry48 and that sulfonyl radicals add quickly to multiple bonds (vide infra) makes cyclization of sulfonyl radicals a rather attractive area. Recently, Johnson and Derenne49 studied the reaction of 6-methylhept-5-en-2-ylcobaloxime(III) with sulfur dioxide and, based on the product analysis, they suggested reaction 15 to be an intermediate step. 

The submitters report that this free radical cyclization was also effected by heating a solution of 5.00 g. (0.026 mole) of ethyl (E)-2-cyano-6-octenoate and 1.25 g. (0.0086 mole) of di-ferf-butyl peroxide [bis(l,l-dimethylethyl)peroxide] in 500 ml. of freshly distilled cyclohexane at 140° in an autoclave for 30 hours. The solution was concentrated and the residue was distilled to yield 3.4 g. (68%) of ethyl l-cyano-2-methylcyclohexanecarboxylate. 

Formaldehyde [Formalin], 55, 45 Foimamide, AJV-dimethyl-, 55,58 FREE RADICAL CYCLIZATION, 55, 57... 

The selection of the thirty procedures clearly reflects the current interest of synthetic organic chemistry. Thus seven of them illustrate uses of T1(I), T1 (III), Cu(I), and Li(I), and three examples elaborate on the process now termed phase-transfer catalysis. In addition, newly developed methods involving fragmentation, sulfide contraction, and synthetically useful free radical cyclization arc covered in five procedures. Inclusion of preparations and uses of five theoretically interesting compounds demonstrates the rapid expansion of this particular area in recent years and will render these compounds more readily and consistently available. 

Free radical cyclization of alkenes with tin or mercury halides... 

N- lomoallylic enamides 239 derived from pymvate were subjected to free radical cyclization in presence of R3SnH and AIBN. The radical species generated from the C-halogen bond homolytic cleavage underwent a 5-endo-cyclization followed either by a 5-exo- or 6-fV/z/o-cyclization and reduction of the final radical species (Scheme 63)... 

Radical cyclization to macrolides.111 Cyclization of iodoalkyl acrylates (1) by reaction with Bu3SnH (1 equiv.) in the presence of AIBN is useful for formation of macrolides (2) containing 11 or more members. Similar cyclization of iodoalkyl fumarates (3) results in two macrolides with the endo-product predominating except when n is 16 or higher. Tertiary iodides undergo this free radical cyclization more... 

Free-radical cure mechanism, silicone network preparation via, 22 568-569 Free-radical cyclization process, 27 147 Free-radical-initiated polymerization, 20 211... 

Allenes have also been used as substrates in free radical cyclizations. Dener and Hart demonstrated that such entries are valuable in constructing pyrrolizidine and indolizidine ring systems [71]. In a total synthesis of pyrrolizidine base (+)-heliotri-dine (340), compound 338 possessing an allene functionality was used as a key intermediate (Scheme 19.62). Tri-n-butyltin radical-mediated carbon-selenium bond homolysis of 338 followed by the addition of the free radical to the allene moiety... 

Whereas the design and application of free radical cyclization reactions have been extensively covered in excellent reviews [3-5], there is no comprehensive report on the synthetic application of their charged counterparts radical cations and radical anions. 

The PET-oxidative cyclization of unsaturated O-alkyl-O-trimethylsilyl ketene acetals 23 and 27 yields cyclic esters 24, 25, and 28, accompanied by the formation of considerable amounts of non-cyclic esters 26 and 29, respectively [89], The cyclization mode is found to be in accordance with free radical cyclizations of the appropriate esters 26 and 29, performed by heating with organic peroxides [90]. Since organic electrochemistry can be used to oxidize... 

Free-radical cyclization on to unsaturated CN bonds and also the cyclization of a range of nitrogen-centred radicals have continued to attract interest and have been reviewed. Aryl radicals, generated from BusSnH- or TTMSS-mediated homolytic cleavage of aryl-bromide bonds, have been shown to cyclize on to the nitrogen atom of imidate esters in the 5-exo mode (Scheme 9). Loss of an ethyl radical leads to the observed A-acylindolines. No cyclization in the 6-endo mode was detected. 

The combination of allylic amination, ring-closing metathesis, and a free radical cyclization provides a convenient approach to the dihydrobenzo[b]indoline skeleton, as illustrated in Scheme 10.10. The rhodium-catalyzed aUylic amination of 43 with the lithium anion of 2-iodo-(N-4-methoxybenzenesulfonyl)arrihne furnished the corresponding N-(arylsulfonyl)aniline 44. The diene 44 was then subjected to ring-closing metathesis and subsequently treated with tris(trimethylsilyl)silane and triethylborane to afford the dihydrobenzojhjindole derivative 46a in 85% yield [14, 43]. 

Conversion of 2-chloroacetamides 17 into iodoacetamides by iodide exchange followed by reaction with BusSnH in the presence of AIBN affords 7,12-dihydro-indolo[3,2-d][l]benzazepin-6(5H)-ones 18 as products of free radical cyclization (Equation (4) (2005T5489)). Low (8-25%) yields of azepinones 18 are observed in toluene medium, and they are usually accompanied with the product of spiro cyclization 19 and isomeric compound 20. Yields of the paullone 18 can be increased to 25-52% at higher temperatures (boiling mesitylene). 

Free-radical cyclizations using ethyl radicals generated by EtsB/air system or stannyl radicals systems provide a range of carbocyclic and heterocyclic hydroxylamines (equation 77). Stereoselectivity in these reactions is variable but can be semiquaUtatively predicted by Beckwith-Houk models . Depending on the substitution pattern of the emerging cyclic system, stereoselectivity can be very high, especially in fused polycyclic systems (equation... 

A free radical cyclization of oxime ethers tethered to an aldehyde has been used in the synthesis of azepine derivatives . For example, oxime ether 389 is cyclized to azepine 390 by reaction with Sml2 in HMPA and f-BuOH at —78°C (equation 170) . Similar free radical cyclization of oxime ethers can be carried out also in the presence of Bu3SnH/AIBN in benzene . Oxime 0-methyl ether 391 underwent thermal cyclization in refluxing o-dichlorobenzene (ODCB) leading to the mixture of two products 392 and 393 in ratio 69 31 in overall yield of 91% (equation 171) °. Rearrangement of oxime 0-tosylates in the presence of piperidine also leads to azepine ring formation . ... 

The /3-lactam fused system (319) has recently been prepared in moderate yield by the free radical cyclization shown (81TL2689, 2693). 

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